Project Summary/Abstract Frontotemporal degeneration (FTD) is an understudied spectrum of neurodegeneration associated with pathologies involving variants of FTLD-Tau or FTLD-TDP. Preliminary cellular and animal studies investigating the cause of progression from Projects 3 and 4 are consistent with spreading cell-to-cell transmission of disease protein, although this has not been examined in humans. In this Project, we use longitudinal clinical (Clinical Core B), neuroimaging with MRI and PET-Tau (Clinical Core B), and genetic (Project 2 and Genetics Core C) information from an established longitudinal FTD cohort supported by this PPG to examine mechanisms of disease progression in humans with Biostatistics and Database Core E, and evaluate this in the context of pathological assessment with Project 4 and Neuropathology & Biomarker Core D. Aim 1 investigates multimodal biomarkers that reflect spreading FTLD pathology during life. We use novel, statistically powerful, and multivariate integration of clinical, MRI and PET-Tau measures available in Penn's multimodal dataset to chart the longitudinal anatomic progression of disease spread in retrospective and prospective cohorts of patients with likely FTLD-Tau compared to FTLD-TDP, and explore progression in FTLD-Tau subgroups with CBD and PSP. We cross-validate clinical and neuropathological staging with autopsied FTLD-Tau patients from Project 4. We hypothesize that multivariate analyses will show an anatomically-constrained imaging pattern of longitudinal disease spread in FTLD-Tau that differs from FTLD- TDP. Aim 2 studies genetic mechanisms that modulate disease progression rate in FTD. With Project 2 and Core C, we associate a risk allele in the region coding for myelin oligodendrocyte basic protein (MOBP) with more rapid progression in FTLD-Tau, and this is related to white matter integrity in imaging studies of FTLD- Tau. We will identify other genetic markers that modulate rate of disease spread, and relate these to cognition and imaging that reflect clinical decline. We hypothesize that additional genetic, biofluid and pathologic mechanisms modulating the rate of disease progression will be identified. Aim 3 studies cognitive reserve factors that modulate rate of clinical progression in FTD. With Cores B, D and E, we examine the way in which education and job attainment impact the rate of progressive clinical decline, and imaging of anatomic mechanisms that support cognitive adaptations to progressive disease. We hypothesize that the rate of longitudinal clinical decline depends in part on professional and educational attainment related to adaptive executive resources. Together with Project 2 and Cores B, C, D and E, this proposal will validate mechanisms of cell-to-cell disease spread in human FTLD based on cell/animal studies in Projects 3 and 4, and will sharpen our understanding of the rate of progression.